1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ANDEXXA safely and effectively. See Full Prescribing Information for ANDEXXA. ANDEXXA ® (coagulation factor Xa (recombinant), inactivated-zhzo) Lyophilized Powder for Solution For Intravenous Injection Initial U.S. Approval: 2018 WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATHS See full prescribing information for complete boxed warning Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including: (5.1) Arterial and venous thromboembolic events Ischemic events, including myocardial infarction and ischemic stroke Cardiac arrest Sudden deaths Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed. __________________ INDICATIONS AND USAGE _________________ ANDEXXA, coagulation factor Xa (recombinant), inactivated-zhzo is a recombinant modified human Factor Xa (FXa) protein indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. (1) This indication is approved under accelerated approval based on the change from baseline in anti-FXa activity in healthy volunteers. An improvement in hemostasis has not been established. Continued approval for this indication may be contingent upon the results of studies to demonstrate an improvement in hemostasis in patients. (1,14) Limitation of Use ANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa inhibitors other than apixaban and rivaroxaban. (1) ______________ DOSAGE AND ADMINISTRATION _______________ For intravenous use only. Dose ANDEXXA based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient’s last dose of FXa inhibitor. (2) Administer as an intravenous (IV) bolus, with a target rate of 30 mg/min, followed by continuous infusion for up to 120 minutes. There are two dosing regimens: Dose* Initial IV Bolus Follow-On IV Infusion Low Dose 400 mg at a target rate of 30 mg/min 4 mg/min for up to 120 minutes High Dose 800 mg at a target rate of 30 mg/min 8 mg/min for up to 120 minutes *The safety and effectiveness of more than one dose have not been evaluated. _____________ DOSAGE FORMS AND STRENGTHS ______________ ANDEXXA is available as a lyophilized powder in single-use vials of 100 mg of coagulation factor Xa (recombinant), inactivated-zhzo. (3) ___________________ CONTRAINDICATIONS ___________________ None. (4) _______________ WARNINGS AND PRECAUTIONS _______________ Arterial and venous thromboembolic events, ischemic events, and cardiac events, including sudden death, have occurred during treatment with ANDEXXA. Resume anticoagulant therapy as soon as medically appropriate following treatment with ANDEXXA. (5.1) Re-elevation or incomplete reversal of anticoagulant activity can occur. (5.2) ___________________ ADVERSE REACTIONS ___________________ The most common adverse reactions (≥ 5%) in patients receiving ANDEXXA were urinary tract infections and pneumonia. (6.1) The most common adverse reactions (≥ 3%) in healthy volunteers treated with ANDEXXA were infusion-related reactions. To report SUSPECTED ADVERSE REACTIONS, contact Portola Pharmaceuticals, Inc. at 1-866-777-5947 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATH 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dose 2.2 Reconstitution 2.3 Administration 2.4 Restarting Antithrombotic Therapy 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Thromboembolic and Ischemic Risks 5.2 Re-elevation or Incomplete Reversal of Anti-FXa Activity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the Full Prescribing Information are not listed.
14
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DOSAGE AND ADMINISTR ATION For intravenous … · See 17 for PATI ENT COUNSELING ... To ensure dissolution of the cake or ... anticoagulated with rivaroxaban had baseline anti-FXa
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1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ANDEXXA safely and effectively. See Full Prescribing Information for
ANDEXXA.
ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo)
Lyophilized Powder for Solution For Intravenous Injection
Initial U.S. Approval: 2018
WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS,
CARDIAC ARREST, AND SUDDEN DEATHS
See full prescribing information for complete boxed warning
Treatment with ANDEXXA has been associated with serious and
life-threatening adverse events, including: (5.1)
Arterial and venous thromboembolic events
Ischemic events, including myocardial infarction and ischemic
stroke
Cardiac arrest
Sudden deaths
Monitor for thromboembolic events and initiate anticoagulation when
medically appropriate. Monitor for symptoms and signs that precede
cardiac arrest and provide treatment as needed.
__________________ INDICATIONS AND USAGE
_________________
ANDEXXA, coagulation factor Xa (recombinant), inactivated-zhzo is a
recombinant modified human Factor Xa (FXa) protein indicated for patients
treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. (1)
This indication is approved under accelerated approval based on the change from baseline in anti-FXa activity in healthy volunteers. An improvement in
hemostasis has not been established. Continued approval for this indication
may be contingent upon the results of studies to demonstrate an improvement in hemostasis in patients. (1,14)
Limitation of Use
ANDEXXA has not been shown to be effective for, and is not indicated for,
the treatment of bleeding related to any FXa inhibitors other than apixaban
and rivaroxaban. (1)
______________ DOSAGE AND ADMINISTRATION
_______________
For intravenous use only.
Dose ANDEXXA based on the specific FXa inhibitor, dose of FXa
inhibitor, and time since the patient’s last dose of FXa inhibitor. (2)
Administer as an intravenous (IV) bolus, with a target rate of 30 mg/min, followed by continuous infusion for up to 120 minutes.
There are two dosing regimens:
Dose* Initial IV Bolus Follow-On IV Infusion
Low
Dose
400 mg at a target rate
of 30 mg/min
4 mg/min for
up to 120 minutes
High
Dose
800 mg at a target rate
of 30 mg/min
8 mg/min for
up to 120 minutes
*The safety and effectiveness of more than one dose have not been
evaluated.
_____________ DOSAGE FORMS AND STRENGTHS
______________
ANDEXXA is available as a lyophilized powder in single-use vials of 100 mg of coagulation factor Xa (recombinant), inactivated-zhzo. (3)
___________________ CONTRAINDICATIONS
___________________
None. (4)
_______________ WARNINGS AND PRECAUTIONS
_______________
Arterial and venous thromboembolic events, ischemic events, and cardiac
events, including sudden death, have occurred during treatment with
ANDEXXA. Resume anticoagulant therapy as soon as medically
appropriate following treatment with ANDEXXA. (5.1)
Re-elevation or incomplete reversal of anticoagulant activity can occur.
(5.2)
___________________ ADVERSE REACTIONS
___________________
The most common adverse reactions (≥ 5%) in patients receiving ANDEXXA
were urinary tract infections and pneumonia. (6.1)
The most common adverse reactions (≥ 3%) in healthy volunteers treated with
ANDEXXA were infusion-related reactions.
To report SUSPECTED ADVERSE REACTIONS, contact Portola
Pharmaceuticals, Inc. at 1-866-777-5947 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATH
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dose
2.2 Reconstitution
2.3 Administration
2.4 Restarting Antithrombotic Therapy
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Thromboembolic and Ischemic Risks
5.2 Re-elevation or Incomplete Reversal of Anti-FXa
Activity
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the Full Prescribing Information are not listed.
Note: Baseline is the last assessment obtained prior to the first dose of ANDEXXA or placebo. a Nadir is the smallest value for anti-FXa activity at the 110 minute (10 minutes prior to the end of the infusion) time
point, 2-minute time point before completion of the infusion, or the 5 minute time point after the completion of the
infusion for each subject. b The CI is for the Hodges-Lehman estimate of shift.
c p-value obtained from a 2-sided exact Wilcoxon rank-sum test.
13
Figure 1: Change in Anti-FXa Activity (ng/mL) in Subjects Anticoagulated with
Apixaban (A – Study 1) and Rivaroxaban (B – Study 2)
(A)
(B)
Anti-FXa activity was measured prior to and after ANDEXXA or placebo administration.
Dashed lines indicate the end of the bolus or infusion. A break in the x-axis is added to better visualize the
immediate, short-term dynamics of anti-FXa activity following ANDEXXA treatment. The points on the graph
represent the mean anti-FXa activity level; error bars illustrate standard error. There was a statistically significant
difference (p < 0.05) in the percent change of anti-FXa activity normalized to pre-bolus between ANDEXXA and
placebo until 2 hours after administration of infusion.
A. Apixaban – with ANDEXXA 400 mg IV bolus plus 4 mg/min infusion for 120 minutes.
B. Rivaroxaban – with ANDEXXA 800 mg IV bolus plus 8 mg/min infusion for 120 minutes.
ANNEXA-4 (NCT02329327)
In an ongoing multinational, prospective, single-arm, open-label study, ANDEXXA was
administered to patients taking FXa inhibitors who presented with acute major bleeding.
T im e a fte r b o lu s (h r)
An
ti-f
Xa
(n
g/m
L)
0 .0 0 .2 0 .4 0 .6
0
5 0
1 0 0
1 5 0
2 0 0
2 5 0
2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4
E n d o f B o lu s
P la c e b o b o lu s + 2 h r in fu s io n (n = 8 )
A N D E X X A 4 0 0 m g b o lu s + 4 8 0 m g x 2 h r in fu s io n (n = 2 3 )
E n d o f In fu s io n
T im e a fte r b o lu s (h r)
An
ti-f
Xa
(n
g/m
L)
0 .0 0 .2 0 .4 0 .6
0
1 0 0
2 0 0
3 0 0
4 0 0
2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4
E n d o f B o lu s
P la c e b o b o lu s + 2 h r in fu s io n (n = 1 3 )
A N D E X X A 8 0 0 m g b o lu s + 9 6 0 m g x 2 h r in fu s io n (n = 2 6 )
E n d o f In fu s io n
14
Interim results of the study include data for 185 patients. Of the 185 patients, 129 were
considered efficacy-evaluable, defined as patients who: 1) were dosed with ANDEXXA; 2) had a
baseline anti-FXa activity above 75 ng/mL; and 3) were adjudicated as meeting eligibility
criteria for acute major bleeding. [also see Adverse Reactions (6)].
For anti-FXa activity, the median decrease from baseline to nadir was -93% for apixaban
and -90% for rivaroxaban. ANDEXXA has not been shown to be effective for bleeding related to
any FXa inhibitors other than apixaban and rivaroxaban.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
ANDEXXA is supplied in cartons of 4 single-use vials each containing 100 mg of ANDEXXA
as a white to off-white lyophilized cake or powder.
NDC 69853-0101-1
Storage and Handling
Unopened vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE.
17 PATIENT COUNSELING INFORMATION
Inform patients that reversing FXa inhibitor therapy increases the risk of thromboembolic events.
Arterial and venous thromboembolic events, ischemic events, cardiac events, and sudden death
were observed within 30 days following ANDEXXA administration. [see Warnings and